Process for preparing sterile radioactive material of the parentdaughter type



April 22, 1969 G, BRUNO ET AL 3,440,423

PROCESS FOR PREPA G STERILE RADIOACTIVE MATERIAL OF THE PARENT-DAUGHTERTYPE Filed April 10, 1967 Sheet of 5 INVENTORS. GERALD A. BRU/VO THOMASA. HANEY PA UL NUME/iOF KARL RE/NHARDT ATTO/PNEV Aprll 22, 1969 G. A.BRUNO ET AL 3,440,423

PROCESS FOR PREPARING STERILE RADIOACTIVE MATERIAL OF THEPARENT-DAUGHTER TYPE Filed April 10, 1967 Sheet 2 of s INVENTORSI GERALDA. BRUNO THOMAS A. HANEV PAUL NUMEROF KARL RE/NHARDT A TTORNEV April 22,1969 BRUNO ET AL 3,440,423

PROCESS FOR PREPARING STERILE RADIOACTIVE MATERIAL I OF THEPARENT-DAUGHTER TYPE Filed April 10, 1967 Sheet 3 of :5

'5 INVENTORS.

GERALD A. BRUNO THOMAS A. HANEY PAUL NUMEROF NA R1. RE/NHA RD T ATTORNEV United States Patent PROCESS FOR PREPARING STERILE RADIO- ACTIVEMATERIAL OF THE PARENT- DAUGHTER TYPE Gerald A. Bruno, Shrewsbury,Thomas A. Haney, East Brunswick, Paul Numerof, Highland Park, and KarlReinhardt, Milltown, N.J., assignors to E. R. Squibb &

Sons, Inc., New York, N.Y., a corporation of DelawareContinuation-impart of application Ser. No. 540,689, Apr. 6, 1966. Thisapplication Apr. 10, 1967, Ser. No. 629,782

The portion of the term of the patent subsequent to Feb. 13, 1985, hasbeen disclaimed and dedicated to the Public Int. Cl. G21h 5/00; (209k1/28; Ctllg 1/00 U.S. Cl. 250106 Claims ABSTRACT OF THE DISCLOSURE Thisinvention relates to a new process for preparing sterile radioactivematerial and essentially entails using a closed sterile system for thepreparation of radioactive material and its recovery. To achieve this acolumn of elutable radioactive material, closed at both ends bypierceable closures, preferably made from resilient material ismaintained in a sterile condition. By use of a closed system such as oneconsisting of the column, a hypodermic syringe containing a sterileeluting solution, a hypodermic needle therefor, that is used to passthrough the aperture in the closure and pierce the top of the column sothat the solution can be' introduced into the top of the column, a tubecontaining hypodermic needles at both ends, one needle of which isinserted into the bottom of the column and the other needle through theclosure of an empty scealed vial which is also pierced by anotherhypodermic needle open to the atmosphere through a sterile plug ofcotton, a sterile system for eluting the column and recovering theeluate containing the desired radioactive material is achieved. Thepreferred radioactive material contains the element M0 yieldingradioactive technetium as the eluted radioactive material.

This application is a continuation-in-part of our application, Ser. No.540,689, filed Apr. 6, 1966, now US. Patent No. 3,369,121.

This invention relates to a new process for preparing sterileradioactive material and essentially entails using a closed sterilesystem for the preparation of radioactive material and its recovery.

The use of radioactive isotopes for the diagnosis and treatment ofvarious medical conditions is well known. Unfortunately, however,certain radioactive isotopes have so short a half-life that they cannotbe economically shipped from the manufacturer to the attendingphysician.

This has made it necessary for the physician to prepare such isotopes asand where they are to be used. One such isotope is the 99m isotope oftechnetium which is used for the localization of brain tumors, forexample. For a more detailed discussion of the subject, reference ismade to an article by Smith in the Journal of Nuclear Medicine, volume5, pages 871-882 (1964). This isotope has a halflife of six hours and isobtained as the daughter product of molybdenum M0 It is separated in theform of the pertechnetate ion from M0 absorbed on an alumina column, byelution with dilute hydrochloric acid or saline. Since maximum growth ofradioactivity of the Tc occurs in about 23 hours, a column containing Momay be eluted daily to yield T0 Because of its high radioactivity, suchcolumn must be shielded at all times to prevent unnecessary exposure toits radioactivity.

Prior to this invention, such columns were in the form of open endedcylinders and were shipped in shielding containers, made of lead or alead salt or other material used as a gamma ray shielding agent. In use,such columns were removed from the containers. The eluate was collectedin a collecting container, such as a beaker or vial, and had to besterilized prior to use, either in situ by use of a sterile filter,which did not insure non-pyrogenicity, or as a separate step, therebyincreasing both the hazard and difiiculty in using such a generatorsystem.

It is an object of this invention, therefore, to provide a novel processfor preparing and recovering radioactive material, whereby a column ofradioactive material can be eluted to yield a sterile, non-pyrogenicradioactive eluate, thereby obviating the need for a subsequentsterilization step.

It is another object of this invention to provide a novel process forpreparing and recovering radioactive material, whereby a column ofradioactive material enclosed in a radioactive sheilding container canbe eluted without necessitating removal of the column from thecontainer.

These objects are achieved by the processes of this invention usingnovel columns and containers, preferred embodiments of which areillustrated in the accompanying drawing wherein:

FIGURE 1 is a perspective view of the separated components that compriseone embodiment of the package of this invention;

FIGURE 2 is an axial section view of the package shown in FIGURE 1, withthe components assembled and the package closed;

FIGURE 3 is an elevational view showing the equipment used to load andwash the column of the package of FIGURE 1 of this invention;

FIGURE 4 is a perspective view of the separated components that comprisea second embodiment of the package of this invention; and

FIGURE 5 is an axial section View of the package shown in FIGURE 4,showing the package in use.

Considering the embodiment shown in FIGURES 1, 2 and 3 of the drawings,the package of this invention comprises generally a container having abody 1, a removable top closure 2, and a radioactive column 3 positionedinside the body 1. Since the principal purpose of the container is tostore radioactive material, the container is fabricated of lead or othermaterial used as a gamma ray shielding material, such as a lead-antimonyalloy iron, or a lead salt, such as lead carbonate or lead sulfide,embedded in plastic. The body 1 is of generally cylindrical shape havinga 'hollow center 4 preferably of circular cross-section and of greaterdiameter than that of column 3. When the column is placed inside thecontainer, the space between the column and the inner Wall of body 1 ispreferably filled with a shock absorbant packing material 5, such ascorrugated paper, foam plastic or a plastic sleeve.

To permit access through the bottom of the container and limited accessthrough the top of container, without removing top closure 2, both thebottom wall and the top closure have centrally positioned apertures 6and 7, sealed by removable plugs 8 and 9, which are also fabricated ofgamma shielding materials.

After column 3 has been placed in the body of the container, thecontainer is closed at its top by means of removable closure 2. In theembodiment shown in the drawing, the closure is retained on the body bymeans of a pair of lugs 10, 10, having enlarged heads 11, 11. Theclosure 2 is equipped with a pair of arcuate keyhole shaped slots 12,12, the enlarged openings of which are of greater diameter than are theheads 11. These slots are countersunk so that the outer portions thereofare of suflicient width to accommodate the heads, whereas the innerportions thereof are of width smaller than the heads 11, but ofsufficient width to accommodate the shank portions of lugs 10. Theclosure is also fabricated of lead or other material relativelyimpervious to radioactivity and, to insure a tight fit with body 1, theclosure is equipped on its inner surface with a circular projection 13having a circumference slightly less than the circumference of thehollow center.

Although in the preferred embodiment, the closure 2 is retained on thebody by means of lugs and keyhole shaped slots, other means may be usedto removably connect the closure to the body. Thus, the closure may besimply taped or stapled to the body, or threading may be used.

The column 3 is preferably made principally of glass or a transparentplastic material and is composed of a cylindrical tube 14 closed at itstop and bottom by means of stoppers 15 and 16. These stoppers arepreferably fabricated of resilient material, such as rubber, that can bepierced by a hypodermic needle, and are held permanently in place bymeans of a pair of annular aluminum discs 17 and 18 that pass over theouter edges of the stoppers, the sides of the stoppers and are thencrimped to the adjacent walls of tube 14, as shown in FIGURE 2. Topermit easy access by air to the inside of tube 14, the bottom stopper16 is equipped with a breather tube 19 that passes through stopper 16 toabout half the height of tube 14. So that the outside end of thebreather tube 19 is in communication with the atmosphere (after removalof plug 8) even when the column 3 is seated in body 1, the bottomstopper 16 is equipped on its outer surface with a groove 20 extendingat least from the outer end of breather tube 19 to aperture 6. To assuresterility, the breather tube 19 is equipped with a plug 21 of cotton orsimilar material.

The tube 14 is equipped with a partition 22 which divides the tube 14into an upper and lower portion. This partition is preferably integralwith the tube 14 along its outer end and tapers downward toward thebottom of tube 14 so as to provide a restricted opening 23 at its lowerend. The partition can be and preferably is fabricated of the samematerial as tube 14. Although the exact position of the partition intube 14 is not critical, it is preferably positioned in the upper halfof tube 14 in such a way that the restricted opening 23 is slightlybelow the upper end of breather tube 19.

Seated on the upper end of partition 22 is a perforated disc 24(preferably a glass fritted disc) on which preferably rests a filter pad25. Resting on top of disc 24, or the filter pad 25, if one is used, isa granulation 26 of a radioactive containing alumina, and optionallyalso a cation exchange resin, such as DoweX-SO-X-S, to prevent passageof the alumina through the tube during elution.

The granulation 26 can be retained in place either by use of aperforated disc (preferably a cloth disc 27 retained in place by aretaining ring 28), as shown in the drawing, or merely by means ofstopper 15.

To prepare the column 3 for use, the granulation 26 is packed into thetop portion of the column, the stoppers 15 and 16 are inserted andcrimped into place by means of aluminum discs 17 and 18. As shown inFIGURE 3, the top stopper 15 is then pierced by two hollow needles 29and 30, one of which is connected to a reservoir 31 and the other to atube 32 open at its other end to the atmosphere. A third hollow needle33 is inserted through bottom stopper 16 to allow for drainage.

To load the column, the reservoir 31 is filled with a source ofradioactivity, such as an aqueous solution of radioactive (M ammoniummolybdate, and the solution is permitted to drip through needle 29 ontoand through granulation 26. Most of the radioactive molybdenum isadsorbed in the granulation. The excess molybdenum and water passthrough the column and are removed through drainage needle 33. Thecolumn is then washed with acid and saline to remove any non-adsorbedmolybdenum, the needles 29, 30 and 33 are removed, and the column issterilized, as by autoclavin g.

The column 3 is inserted into body 1. The closure 2 is then sopositioned over the top of body 1 that the lugs pass through theenlarged portions of slots 9, and rotated to firmly connect the closuresto said body. The package is then ready for shipment.

When the package is to be used, the plugs 8 and 9 are removed and thecolumn 3 is then eluted, by injecting a sterile, non-pyrogenic elutingsolution, such as sterile, nonpyrogenic isotonic saline, through the topstopper 15 into the upper portion of tube 14. The injection isaccomplished by passing the needle of a hypodermic syringe containingthe eluting solution through aperture 7 and through stopper 15. Theeluate, containing the radioactive material, is collected and maintainedin the bottom of tube 14. When the eluate is to be used, it is removedfrom tube 14- by piercing the stopper 16 with a sterile hypodermicneedle (connected to a syringe) by passing the needle through aperture 6and stopper 16.

Considering now the embodiment shown in FIGURES 4 and 5 of the drawings,the package of this embodiment of the invention differs from the firstembodiment primarily in the omission of the lower chamber in the column.It comprises generally a container having a body 101, a removable topclosure 102, and a radioactive column 103 positioned inside the body101. The body 101 and closure 102 are fabricated from gamma rayshielding material as described hereinbefore. The body 101 is ofgenerally cylindrical shape having a hollow center 104 preferably ofcircular cross-section and of greater diameter than that of column 103.When the column is placed inside the container, the space between thecolumn and the inner wall of body 101 is preferably filled with a shockabsorbant packing material 105, such as corrugated paper, foam plasticor a plastic sleeve.

To permit access through the bottom of the container and limited accessthrough the top of the container, without removing top closure 102, boththe bottom wall and the top closure have centrally positioned apertures106 and 107, sealed by removable plugs 108 and 109, which are alsofabricated of gamma shielding materials.

After column 103 has been placed in the body of the container 101, thecontainer is closed at its top by means of removable closure 102. Thismay be done by positioning the closure 102 on the cotnainer 101 andafiixing it by means of a strip of adhesive tape (not shown) or othermeans. To assure a tight fit, the closure 102 is equipped on its innersurface with a circular projection 113 having a circumference slightlyless than the circumference of the hollow center.

The column 103 is preferably made principally of glass or a plasticmaterial and is composed of a cylindrical tube 114 closed at its top andbottom by means of stoppers 115 and 116. These stoppers are preferablyfabricated of resilient material, such as rubber, that can be pierced bya hypodermic needle and are held permanently in place by means of a pairof annular aluminum discs 117 and 118 that pass over the outer edges ofthe stoppers, the sides of the stoppers and are then crimped to theadjacent walls of tube 114, as shown in FIGURE 5,

Positioned in the tube 114, preferably spaced from but near the bottomthereof, is a perforated disc 124 (preferably a glass fritted disc) onwhich preferably rests a filter pad 125. Resting on top of disc 124, orthe filter pad 125 if one is used, is a granulation 126 of the samematerial used in the first embodiment. The granulation 126 can beretained in place either by use of a perforated disc 127, as shown inFIGURES 4 and 5 of the drawing, or merely by means of stopper 115.

The column is prepared for use by the same method used in the firstembodiment of this invention, as shown by FIGURE 3. The loaded column103 is then inserted into body 101 and the closure 102 is positionedover the opening in .body 101 and retained thereon by means of anadhesive strip or other means. The package is then ready for shipment.

When the package is to be used, the plugs 108 and 109 are removed andthe column 103 is eluted, by injecting a sterile, non-pyrogenic elutingsolution, such as sterile, non-pyrogenic isotonic saline, through thetop stopper 115 into the upper portion of tube 114. The injection is!accomplished by passing the needle of a hypodermic syringe (not shown)containing the eluting solution through aperture 107 and through stopper115. The elute, containing the radioactive material, is withdrawn formthe bottom of tube 114 by means of a hypodermic needle 34. This needle34 passes through aperture 106 and bottom stopper 116 into the spacebetween perforated disc 124 and stopper 116. To increase this space,stopper 116 is preferably fabricated to have a concave center portion35.

The under end of needle 34 is connected through tubing 36 to a secondhypodermic needle 37 that passes into a sterile empty vial or othercontainer 38 through a rubber stopper 39 closing the vial and retainedthereon by means of a crimped anular aluminum disc 40. To permit the airin the vial to escape as the eluate flows into the vial, the stopper 39is also pierced by a third hypodermic needle 41, exposed to theatmosphere. To assure sterility of the system, needle 41 is equippedwith a plug 42 of cotton or similar material, To minimize the exposureto radiation, vial 38 is retained in a shield 43 of gamma ray shieldingmaterial,

In use, the eluate passes from column 103 through needle 34, tubing 36,and needle 37 into vial 38. When the eluate is to be used, it is removedfrom vial 38 by piercing the stopper 39 with a sterile hypodermic needle(connected to a syringe).

Although in both embodiments of this invention, the closures 2 and 102are designated as top closures, the columns 3 and 103, respectively, canof course be introduced upside down into the bodies 1 and 101, in whichcase the top closure becomes a bottom closure.

By use of the packages of this invention it is possible to carry out theentire elution operation under sterile conditions without ever removingthe column 3 or 103 from the protective shield, thereby minimizing thepossibility of exposure to the relatively high radioactivity of thecolumn. Furthermore, since the whole eluting operation is carried outunder sterile conditions, the need to sterilize the radioactive eluateprior to use is obviated.

What is claimed is:

1. A process for preparing sterile non-pyrogenic radioactive material,which comprises preparing a closed system containing a source of sterilenon-pyrogenic eluting solution and a column of sterile elutableradioactive material and a sterile collecting container, and elutingsaid column into said container.

2. The process of claim 1, wherein the source of the radioactivematerial contains the element M0 3. The process for preparing sterilenon-pyrogenic radioactive material, which comprises preparing a columnof elutable radioactive material, closed at its top and bottom byclosures and having positioned therein and spaced from the bottomthereof a source of sterile non-pyrogenic elutable radioactive material,passing through said top closure a sterile eluting solution contained ina closed system, and passing the eluate containing the radioactivematerial through said bottom closure into a closed collecting system.

4. The process of claim 3, wherein the source of radioactive materialcontains the element M0 5. The process of claim 4, wherein the closuresare fabricated of resilient material and the sterile eluting solution isintroduced into the column by piercing the top closure with a hypodermicneedle connected to a hypodermic syringe containing the sterile elutingsolution.

6. The process of claim 5, wherein the eluate is removed from the columnby piercing the bottom closure with a hypodermic needle connected to aclosed collecting system.

7. The process of claim 6, wherein the collecting system comprises asterile tube having hypodermic needles at both ends, one needle of whichpierces the bottom closure and the other needle of which pierces aresilient closure of a sterile collecting vial.

8. The process of claim 7, wherein the resilient closure of thecollecting vial is also pierced by a second hypodermic needle sterilelyconnected to the atmosphere.

9. The process of claim 3, wherein the column is retained in a shieldingcontainer having side and bottom walls, said bottom wall containing arestricted aperture therein through which the eluate is passed.

10. The process of claim 9, wherein the container has a removableclosure for the top, said closure having a restricted aperture thereinthrough which the eluting solution is passed.

References Cited UNITED STATES PATENTS 2,892,086 6/1959 Carter 250106 X3,156,532 11/1964 Doering et al. 252-3011 3,369,121 2/1968 Bruno et al.

ARCHIE R. BORCHELT, Primary Examiner.

US. Cl. X.R.

